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Biology subjects

Li, O.

Publications and source records attributed to Li, O..

8 recordsLinked to original sources

GeneJEPA: A Predictive World Model of the Transcriptome

We introduce GO_SCPLOWENEC_SCPLOWJO_SCPLOWEPAC_SCPLOW, a self-supervised foundation model that learns a predictive world model of single-cell transcriptomes. Based on the Joint-Embedding Predictive Architecture, GO_SCPLOWENEC_SCPLOWJO_SCPLOWEPAC_SCPLOW predicts latent representations of masked gene sets from visible context, a shift away from reconstructing noisy expression values and toward world-model style inference over cellular state. To realize this at scale, a Perceiver encoder handles variable gene sets at fixed cost, and a tokenizer jointly represents gene identity and continuous expression using Fourier features. Trained on the Tahoe-100M atlas, GO_SCPLOWENEC_SCPLOWJO_SCPLOWEPAC_SCPLOW learns general representations that transfer across tissues and datasets. On downstream tasks, including drug response and perturbation prediction, it surpasses strong baselines and enables test-time scaling by progressively enlarging the cross-attention over the gene set, trading a small read cost for higher accuracy at inference. GO_SCPLOWENEC_SCPLOWJO_SCPLOWEPAC_SCPLOW moves toward foundation models that reason over gene-gene relations, enabling applications in annotation, prediction, and in-silico discovery.

genomics↗

NTX250: A Modular mRNA-Based Immunotherapy Platform for HPV-Associated Cancers with Broad Applicability.

Infection with high-risk human papillomavirus (HPV) is a key driver of multiple HPV-associated malignancies, including cervical intraepithelial neoplasia (CIN), oropharyngeal, head and neck, and anogenital cancers. Despite the high efficacy of prophylactic HPV vaccines, a substantial population remains at ongoing risk due to issues related to vaccine accessibility, awareness, or personal choice. Current treatments, such as the loop electrosurgical excision procedure (LEEP), address lesions but do not eliminate persistent HPV infection and are associated with potential complications. Moreover, individuals treated for HPV-related disease are at increased risk for subsequent HPV-associated malignancies. These factors underscore an urgent need for effective, non-invasive therapeutic strategies capable of targeting and eradicating persistent HPV infections. Here we introduce NTX250, an innovative mRNA-based therapeutic platform designed to deliver HPV type 16 (HPV16) E6-E7 antigens, combined with immunomodulators human interleukin-12 (IL-12) p70 and engineered human LIGHT (LIGHT). The mRNAs are co-delivered via lipid and ionizable peptoid nanoparticles referred to as Nutshell formulation for intralesional administration. Our preclinical evaluation demonstrates that localized delivery of NTX250 in HPV16-transformed tumor-bearing models results in complete tumor regression and the induction of durable, antigen-specific immune memory. Moreover, this modular mRNA nanoparticle approach combining tumor-specific antigens and immunomodulators is adaptable beyond HPV, with potential applications targeting neoepitopes or other tumor-associated antigens, thus offering a versatile platform for immunotherapy across a broad range of indications. These findings highlight the potential of this strategy as a broadly applicable, non-surgical immunotherapeutic capable of inducing robust and specific anti-tumor responses.

immunology↗

Guided multi-agent AI invents highly accurate, uncertainty-aware transcriptomic aging clocks

Scientific discovery has long relied on human creativity, with computation limited to analysis. Here we report an AI-guided system, K-Dense, that accelerates hypothesis testing and delivers robust scientific discoveries. Trained on ARCHS4 (57,584 samples, 28 tissues, 1,039 cohorts, ages 1-114), the unified ensemble clock achieved R2 = 0.854 and MAE = 4.26 years--while uniquely providing calibrated confidence intervals. This self-aware design flags predictions made at transitional or extreme ages, where biological heterogeneity peaks, suggesting clinical utility for uncertainty itself. Development revealed stage-specific markers, including CDKN2A/p16 (senescence), AMPD3 (muscle wasting), MIR29B2CHG (progeroid traits), and SEPTIN3 (neurodegeneration resistance). Sliding-window analysis across 85 overlapping ranges uncovered wave-like shifts in gene importance, showing that transcriptomic aging signatures evolve continuously, not discretely. By transforming biological age assessment from static point estimates to calibrated predictions with explicit uncertainty, this approach establishes reliable and interpretable clocks. Beyond the clock itself, K-Dense demonstrates how guided AI can compress months of exploration into weeks, pointing toward a scalable framework for accelerated scientific discovery.

systems biology↗

A Single-cell and Spatially Resolved Cell Atlas of Human Esophageal Squamous Cell Carcinoma

Tumor heterogeneity and the suppressive microenvironment are key challenges that limit the effectiveness of cancer treatment. In this study, we systematically elucidated the molecular characteristics and mechanisms underlying the suppressive immune microenvironment via a combination of single-cell RNA sequencing, spatial transcriptomics, and metabolomics for a series of human esophageal squamous cell carcinoma (ESCC) and matched nontumor tissues. We found that COL17A1+ epithelial cells presented greater malignancy, characterized by triglyceride (TG) and phosphocholine (PC) accumulation. We also identified a tumor-specific POSTN+ fibroblast subgroup. We found a unique epithelial-fibroblast niche with low infiltration of effector immune cells and substantial enrichment of lipids, composed of POSTN+ fibroblasts and COL17A1+ epithelial cells, where their crosstalk contributed to tumor progression. We confirmed that the INHBA/TP63 axis plays a key role in mediating the regulation of COL17A1+ tumor cells by POSTN+ fibroblasts. Our findings provided new insights into the characteristics of the tumor microenvironment and the crosstalk between tumor and fibroblasts, offering valuable multiomics data resources for elucidating tumor progression mechanisms.

genomics↗

High-throughput Monoclonal Antibody Screening from Immunized Rabbits via Droplet Microfluidics

The discovery of monoclonal antibodies (mAbs) is critical to advancing therapeutics, diagnostics, and biomedical research. While mouse-derived mAbs dominate current applications, their limitations--short serum half-life, human immunogenicity, and restricted recognition of human-specific antigens--underscore the need for alternative sources. Rabbit-derived mAbs have been gaining significant traction with their superior antigen-binding affinity, broader epitope diversity, and higher yield potential. However, the absence of well-defined surface markers on rabbit B cells has hindered efficient enrichment strategies, limiting the exploration of this valuable antibody repertoire. In this study, we present an integrated workflow that combines magnetic negative selection with high-throughput droplet microfluidics to overcome these barriers. By optimizing a pan B cell enrichment protocol using a tailored antibody cocktail, we achieved a notable boost in IgG secretion and B cell enrichment. Through two complementary droplet-encapsulated assays using particle aggregation for soluble antigens and reporter cells for membrane-bound antigens, we identified target cells capable of secreting high-affinity IgGs. Subsequent sequencing, in vitro antibody production and characterization confirmed the high affinity rate of the discovered antibodies, outperforming rates previously reported. The use of droplet microfluidics streamlines the analysis of rabbit IgG repertoires, providing a robust platform for rabbit single B cell antibody discovery with promising applications in precision medicines and diagnostics.

molecular biology↗

METTL1/WDR4-mediated m7G Hypermethylation of SCLT1 mRNA Promotes Gefitinib Resistance in Non-small Cell Lung Cancer

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have produced durable complete responses, but the eventual development of acquired resistance presents a huge challenge in the treatment of non-small cell lung cancer (NSCLC). N7-methylguanosine (m7G), a prevalent post-transcriptional modification within RNA, play regulatory roles in RNA stability, expression dynamics, and functional diversity. Despite these insights, the contribution of m7G methylation to EGFR-TKIs resistance remains poorly characterized. Here, we identified substantial upregulation of mRNA internal m7G modifications and their associated methyltransferase complex composed of methyltransferase-like 1 (METTL1) /WD repeat domain 4 (WDR4) were significantly elevated in NSCLC specimens, correlating with therapeutic resistance. Functional assays confirmed that METTL1/WDR4 enhances gefitinib resistance in both cellular and animal models via the internal RNA m7G methyltransferase activity in NSCLC. Mechanistically, m7G MeRIP-seq coupled with RNA-seq identified sodium channel and clathrin linker 1 (SCLT1) as the m7G target of METTL1/WDR4. METTL1/WDR4 knockdown may result in a decrease in both the demethylation level and mRNA stability of the SCLT1 transcript, while overexpression of wild-type METTL1, but not its catalytically inactive mutant, rescues mRNA stability. METTL1/WDR4-mediated m7G modification of SCLT1 regulates gefitinib resistance by activating the NF-{kappa}B signaling. These results establish aberrant mRNA internal m7G modification as a novel resistance mechanism and propose therapeutic targeting of the METTL1/WDR4-SCLT1-NF-{kappa}B axis cascade to overcome EGFR-TKIs resistance.

molecular biology↗

BIOFORMERS: A SCALABLE FRAMEWORK FOR EXPLORING BIOSTATES USING TRANSFORMERS

AO_SCPLOWBSTRACTC_SCPLOWGenerative pre-trained models, such as BERT and GPT, have demonstrated remarkable success in natural language processing and computer vision. Leveraging the combination of large-scale, diverse datasets, transformers, and unsupervised learning, these models have emerged as a promising method for understanding complex systems like language. Despite the apparent differences, human language and biological systems share numerous parallels. Biology, like language, is a dynamic, interconnected network where biomolecules interact to create living entities akin to words forming coherent narratives. Inspired by this analogy, we explored the potential of using transformer-based unsupervised model development for analyzing biological systems and proposed a framework that can ingest vast amounts of biological data to create a foundational model of biology using BERT or GPT. This framework focuses on the concept of a biostate, defined as a high-dimensional vector encompassing various biological markers such as genomic, proteomic, transcriptomic, physiological, and phenotypical data. We applied this technique to a small dataset of single-cell transcriptomics to demonstrate its ability to capture meaningful biological insights into genes and cells, even without any pre-training. Furthermore, the model can be readily used for gene network inference and genetic perturbation prediction.

bioinformatics↗

Targeting Thymidine Phosphorylase with Tipiracil Hydrochloride is a Safe and Effective Antithrombotic Therapy

RationaleMost of the current anti-platelet drugs inhibit platelet function permanently and have systemic side effects, including thrombocytopenia and hemorrhage. We previously found that thymidine phosphorylase (TYMP), a platelet cytoplasmic protein, facilitates multiple agonist induced platelet activation and enhances thrombosis. A specific TYMP inhibitor, namely, tipiracil hydrochloride (TPI), has been approved by the U.S. Food and Drug Administration for clinical use as an auxiliary drug making it possible to be repositioned as an anti-platelet medicine. ObjectiveWe aimed to test the hypothesis that TPI is a novel and safe anti-platelet drug by examining its role in platelet activation and thrombosis using both in vitro and in vivo studies. Methods and ResultsBy co-expression of TYMP and Lyn or Lyn-SH3 domain tagged with glutathione S-transferase, we showed the direct evidence that TYMP binds to the SH3 domain in its partners. TYMP haplodeficiency is sufficient to inhibit thrombosis in vivo regardless of gender. TPI treatment rapidly inhibited collagen- and ADP-induced platelet aggregation, which copied the phenotype of TYMP deficient platelets. Under both normal and hyperlipidemic conditions, treating wild type (WT) mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even administered above the effective dose, TPI has a lower bleeding side effect compared to aspirin and clopidogrel. Most importantly, intravenously delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited the growth of developing thrombi. Dual administration of very low dose of aspirin and TPI also dramatically inhibited thrombosis without disturbing hemostasis. ConclusionThis pharmacological study demonstrated that TYMP participates in multiple signaling pathways in platelet and plays a mechanistic role in regulating platelet activation and thrombosis. TPI, a specific TYMP inhibitor, would be a novel safe anti-platelet and anti-thrombosis medicine.

cell biology↗